Fetal Growth Restriction (FGR)

Genetically predetermined fetal growth potential influenced by environmental parameters determines fetal growth and birth weight. These parameters can be physiological (fetal and maternal health and placental function), behavioral (maternal emotional stress), social (socioeconomic status, life-style and malnutrition), and ecological (starvation/famine).

The interaction between genome and environment in the regulation of fetal growth and development constitutes a complex process. Intrauterine adversities challenge the growing fetus, forcing it to reallocate its energy resources between the adaptation to the challenge and growth in order to ensure survival, reproduction enhancement and genome preservation. Thus, FGR is the evolutionary result of adaptation to a suboptimal intrauterine milieu.

FGR occurs in approximately 5% of all human pregnancies and is associated with a substantially increased risk of perinatal mortality and long-term morbidity. The definition of FGR excludes small for gestational age (SGA) fetuses that are constitutionally small.

Based on growth curves, growth-restricted fetuses are considered to be those with estimated weights below the 10th percentile for gestational age, below the 5th percentile for gestational age, or two standard deviations (<3%) below the mean for gestational age. Approximately 80% of fetuses with estimated weights below the 10th percentile for gestational age are constitutionally small (normal small), 15% are starved small due to placental insufficiency, and 5% are abnormal small. The lower the percentile that defines SGA, the higher the likelihood of FGR.

FGR is further categorized as symmetric or asymmetric. Symmetric FGR is characterized by proportional reduction in growth velocity of both the fetal head circumference (HC) and abdominal circumference (AC), indicating a constitutionally small fetus. Symmetric FGR can also be indicative of in utero adversities such as chromosomal abnormalities, genetic syndromes, congenital infections, use of medication or teratogenic agents.

Asymmetric FGR is characterized by a disproportional reduction in growth velocity of the fetal HC to AC and is mainly associated with placental insufficiency. However, body proportionality does not always specify the causes of FGR. Snijders et al. performed fetal blood karyotyping on 458 fetuses between 17 and 39 weeks gestation who had been referred for evaluation of intrauterine growth restriction (IUGR) and they demonstrated that the relative shortening of the femur can be found in both chromosomally normal and abnormal fetuses.

In the same study, fetuses with triploidy had been found to have severe, early-onset, asymmetric FGR, whereas fetuses with chromosomal abnormalities other than triploidy were symmetrically growth retarded at <30 weeks. Chromosomally abnormal IUGR fetuses diagnosed after 30 weeks are usually asymmetrically growth restricted. The authors suggested that the asymmetry results from superimposed starvation due to placental insufficiency.

Placental insufficiency and fetal abnormalities (chromosomal, structural and congenital infections) are responsible for the majority of FGR cases in singleton pregnancies. According to histopathologi- cal studies, placental insufficiency is associated with abnormal trophoblast invasion and villous development that impairs placental vascular function, restricting nutrient and oxygen transfer to the fetus.

The severity of placental insufficiency can be manifested in both maternal and fetal vascular compartments, (uterine and umbilical arteries respectively). The discrepancy between fetal growth demands and environmental conditions, mainly defined by placental vascular dysfunction, determines the severity of the compromised growth velocity that may manifest as FGR or even as fetal demise.

Clinical studies have documented the correlation between increased blood flow impedance in the uterine arteries and the subsequent development of preeclampsia, and FGR. Abnormal Doppler waveform in the uterine arteries is associated with a 70% chance of developing preeclampsia and an approximately 30% chance of developing growth restriction.

In FGR pregnancies increased Doppler indices in the umbilical arteries are associated with fetal hypoxemia and acidemia correlated to the severity of the impedance of the umbilical flow. Fetal cardiovascular adaptations to placental insufficiency result in the redistribution of cardiac output. As a consequence, there is an increase in the blood supply to the brain, myocardium, and the adrenal glands at the expense of the kidneys, gastrointestinal tract, and lower extremities.

The aforementioned redistribution of cardiac output can be documented by the reduced impedance of the blood flow in the middle cerebral artery. Fetuses exhibiting blood flow redistribution are usually hypoxemic, while acidemia may still not be clinically apparent. Further deterioration of fetal circulatory status is manifested by cardiac decompensation due to the exhaustion of adaptive mechanisms to hypoxia, indicated by right heart failure and abnormal organ autoregulation.

Elegant studies investigating the metabolic status of growth-restricted fetuses by cordocentesis have documented fetal compromise by hypoxemia, hypercapnia, hyperlacticemia, and acidosis. Growth-restricted fetuses are deprived of glucose and amino acids and are hypertriglyceridemic. In addition, some of these fetuses are hypoinsulinemic and their degree of hypoinsulinemia is disproportional to the degree of hypoglycemia, suggesting pancreatic dysfunction.

In growth-restricted fetuses, the plasma cortisol concentration is increased and inversely correlated to fetal hypoglycemia. There is evidence of a significant correlation between umbilical cord plasma CRH and both ACTH and cortisol concentrations, as well as a significant negative correlation between CRH and dehydroepiandrosterone sulfate (DHEAS) levels in the growth-restricted fetuses. The umbilical cord plasma CRH level is extremely elevated compared to that of normal fetuses.

Placental CRH synthesis and release, in contrast to hypothalamic CRH, appears to be stimulated by glucocorticoids. In pregnancies complicated by uteroplacental insufficiency, placental CRH production may be enhanced by increased fetal glucocorticoids.

In turn, placental CRH may modulate fetal pituitary- adrenal steroidogenesis to favor increased cortisol secretion. Conditions of chronic stress may stimulate hypothalamic as well as placental CRH, modulating fetal pituitary-adrenal function and consequently fetal response to a compromised intrauterine environment.

In FGR fetuses there is delayed maturation of biophysical parameters is apparent in IUGR fetuses. Fetal behavioral responses to placental insufficiency can affect heart-rate control by delaying the physiological decline of the baseline heart rate and maturation of reactivity and by decreasing short- and long-term variability.